The overall goal of this project is to understand how retroviruses adversely affect the central nervous system and the nature of the role of macrophages in disease pathogenesis. We are utilizing the mouse as an animal model and are investigating two types of neurovirulent viruses that cause different brain diseases. We have studied the host and viral factors which control neuroinvasiveness (the capacity of these viruses to enter the brain), and the determinants of neurovirulence (induction of brain disease) after these viruses have entered the brain. Our work on neuroinvasiveness has uncovered a viral protein that has been known to exist for many years, but its function in the virus life cycle is unknown. We are interested in understanding the function of this protein since it appears to be an accessory protein of the virus that promotes virus dissemination in the host. A fragment of this protein has been found to be incorporated into virions.Our work on neurovirulence has focused on the role of the viral envelope protein and its interaction with microglial cells (brain macrophages). Although these viruses interfere with normal neuronal function and in some cases actually result in neuronal death, they do not infect the neurons they damage. Instead, it is infection of microglial cells (fixed tissue macrophages of the central nervous system) that is responsible for the neurovirulence of these viruses. Furthermore, neurovirulence has been mapped to the viral envelope protein (coat protein of the virus) and we are interested in understanding the nature of the interaction between this protein and microglial cells which appears to play such an important role in disease pathogenesis. This year we have found that the receptor-binding domain of the envelope protein determines the neurovirulence of these viruses, suggesting an important role of the viral receptor, an amino acid transporter, in disease pathogenesis. We have begun, using microarray and real-time PCR technology, to identify host genes which are differentially expressed during early stages of disease. These studies have implicated components of the complement system as well as the possible involvement of the renin-angiotensin system, both of which may also be involved in human neurodegenerative diseases.